New use of 1-amino-alkylcyclohexanes, i.e., as anti-parasitemial, anti-trypanosomiasis, or trypanocidal agents.
Vector control and other public health measures have a successful history of containing African trypanosomiasis. However, war, civil unrest and economic problems have resulted in a breakdown of these interventions and the estimated annual incidence is now 300,000 cases. The causative agents of human trypanosomiasis are the tsetse fly-transmitted protozoan parasites Trypanosoma brucei gambiense (western and central Africa) and Trypanosoma brucei rhodesiense (eastern and southern Africa). In the bloodstream of infected individuals antigenic variation by the parasite prevents elimination by the immune system and the development of a vaccine is not considered feasible. The drugs used to treat trypanosomiasis are unsatisfactory. They all require hospitalization, are expensive, can fail to eradicate parasitemia and often have toxic side effects. Melarsoprol, which is used against the advanced stage of the disease that occurs once trypanosomes have invaded the central nervous system, causes 5 to 10% patient mortality due to arsenic encephalopathy. The only other drug available for clinical use against this stage of the disease, difluoromethylornithine (DFMO), has limited efficacy against T.b. rhodesiense infections and is very expensive. In the absence of treatment, trypanosomiasis is fatal and the development of new chemotherapeutic approaches is thus a priority.
The prior art is represented by our prior U.S. Pat. No. 6,034,134 of Mar. 7, 2000 and our published application WO 99/01416, PCT/EP98/04026, and Parsons et al. Neuropharmacology 38, 85-108 (1999), wherein the active compounds utilized according to the present invention are disclosed and disclosed to be NMDA receptor antagonists and anticonvulsants. We have subsequently disclosed them to be useful as 5HT3 and neuronal nicotinic receptor antagonists.
The present invention is directed to a new use of 1-amino-alkylcyclohexane compounds selected from the group consisting of those of the formula 
wherein R* is xe2x80x94(CH2)nxe2x80x94(CR6R7)mxe2x80x94NR8R9 
wherein n+m=0, 1, or 2
wherein R1 through R7 are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C), and
wherein R8 and R9 each represent hydrogen or lower-alkyl (1-6C) or together represent lower-alkylene xe2x80x94(CH2)xxe2x80x94
wherein x is 2 to 5, inclusive, and enantiomers, optical isomers, hydrates, and pharmaceutically-acceptable salts thereof, as well as pharmaceutical compositions thereof,
and the preparation and use of such compounds and compositions for the treatment of a living animal as antitrypanosomiasis agents and as trypanocides.
Representative of these compounds are as follows:
MRZ 579: 1-Amino-1,3,3,5,5-pentamethylcyclohexane,
580: 3,3,5,5-Tetramethylcyclohexylmethylamine,
601: 1-Amino-1-propyl-3,3,5,5-tetramethylcyclohexane,
607: 1-Amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
614: 3-Propyl-1,3,5,5-Tetramethylcyclohexylamine semihydrate (mixture of diastereomers xcx9c1:2)
615: 1-Amino-1,3,5,5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers),
616: 1-Amino-1,3,5-trimethylcyclohexane (mixture of diastereomers),
617: 1-Amino-1,3-dimethyl-3-propylcyclohexane (mixture of diastereomers),
618: 1-Amino-1,3 (trans),5 (trans)-trimethyl-3(cis)-propylcyclohexane,
620: 1-Amino-1,3-dimethyl-3-ethylcyclohexane,
621: 1-Amino-1,3,3-trimethylcyclohexane,
622: cis-3-Ethyl-1, trans-3, trans-5-trimethylcyclohexamine,
625: 1-Amino-1,3 (trans)-dimethylcyclohexane,
626: 1,3,3-Trimethyl-5,5-dipropylcyclohexylamine,
627: 1-Amino-1-methyl-3 (trans) propylcyclohexane,
628: 1-Methyl-3-cis-propylcyclohexylamine,
629: 1-Amino-1-methyl-3 (trans) ethylcyclohexane,
632: 1-Amino-1,3,3-trimethyl-5 (cis) ethylcyclohexane,
633: 1-Amino-1,3,3-trimethyl-5 (trans) ethylcyclohexane,
634: cis-3-Propyl-1,5,5-trimethylcyclohexylamine,
635: trans-3-Propyl-1,5,5-trimethylcyclohexylamine
639: N-Ethyl-1,3,3,5,5-pentamethylcyclohexylamine,
640: N-methyl-1-Amino-1,3,3,5.5-pentamethylcyclohexane,
641: 1-Amino-1-methylcyclohexane,
642: N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
644: 2-(3,3,5,5-Tetramethylcyclohexyl)ethylamine,
645: 2-Methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,
662: 2-(1,3,3,5,5-Pentamethylcyclohexyl-1) ethylamine, semihydrate
705: N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine,
680: 1-amino-1,3(trans),5(trans)-trimethylcyclohexane,
681: 1-amino-1,3(cis),5(cis)-trimethylcyclohexane, .H2O,
682: 1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane,
683: 1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane, .H2O,
1-Amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane,
1-Amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane,
1-Amino-1-methyl-3 (cis)-ethyl-cyclohexane,
1-Amino-1-methyl-3(cis)-methyl-cyclohexane,
1-Amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane, and
Also, 1-amino-1,3,3,5,5-pentamethylcyclohexane,
1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,
1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,
N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,
N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or piperidine,
N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,
N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,
N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or piperidine,
N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,
N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl] pyrrolidine or piperidine,
N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or piperidine,
N-[(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexyl] pyrrolidine or piperidine,
N-(1-ethyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine, and
N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine,
and optical isomers, enantiomers, and the hydrochloride, hydrobromide, hydrochloride hydrate, or other pharmaceutically-acceptable salts of any of the foregoing.
Of particular interest are compounds of the foregoing formula wherein at least R1, R4, and R5 are lower-alkyl and those compounds wherein R1 through R5 are methyl, those wherein x is 4 or 5, and in particular the compound N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof.
In our U.S. Pat. No. 6,034,134 of Mar. 7, 2000, we disclosed compounds of the foregoing formula, pharmaceutical compositions thereof, and their use as NMDA-receptor antagonists and anticonvulsants. It has now been found that compounds of the foregoing formula and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof, in addition to their NMDA antagonist and anticonvulsant properties, quite unpredictably possess a high degree of anti-trypanosomiasis activity, making them useful in the treatment of trypanosomiasis and as trypanocides.
What we therefore believe to be comprised by our present invention may be summarized, inter alia, in the following words:
A method-of-treating a living animal for inhibition of progression or alleviation of a condition which is alleviated by an anti-trypanosomiasis agent or trypanocide, comprising the step of administering to the said living animal an amount of a 1-aminoalkylcyclohexane compound selected from the group consisting of those of the formula 
wherein R* is xe2x80x94(CH2)nxe2x80x94(CR6R7)mxe2x80x94NR8R9 
wherein n+m=0, 1, or 2
wherein R1 through R7 are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C),
wherein R8 and R9 are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) or together represent lower-alkylene xe2x80x94(CH2)xxe2x80x94wherein x is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically-acceptable salts thereof, which is effective for the said purpose; such a
method wherein at least R1, R4, and R5 are lower-alkyl; such a
method wherein R1 through R5 are methyl; such a
method wherein R1 is ethyl; such a
method wherein R2 is ethyl; such a
method wherein R3 is ethyl; such a
method wherein R4 is ethyl; such a
method wherein R5 is ethyl; such a
method wherein R5 is propyl; such a
method wherein R6 or R7 is methyl; such a
method wherein R6 or R7 is ethyl; such a
method wherein X is 4 or 5; such a
method wherein the compound is selected from the group consisting of
580: 3,3,5,5-Tetramethylcyclohexylmethylamine,
601: 1-Amino-1-propyl-3,3,5,5-tetramethylcyclohexane,
607: 1-Amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
614: 3-Propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate (mixture of diastereomers xcx9c1:2)
615: 1-Amino-1,3,5,5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers),
617: 1-Amino-1,3-dimethyl-3-propylcyclohexane (mixture of diastereomers),
618: 1-Amino-1,3 (trans),5 (trans)-trimethyl-3(cis)-propylcyclohexane,
620: 1-Amino-1,3-dimethyl-3-ethylcyclohexane,
621: 1-Amino-1,3,3-trimethylcyclohexane,
622: cis-3-Ethyl-1, trans-3, trans-5-trimethylcyclohexamine,
625: 1-Amino-1,3 (trans)-dimethylcyclohexane,
626: 1,3,3-Trimethyl-5,5-dipropylcyclohexylamine,
627: 1-Amino-1-methyl-3 (trans) propylcyclohexane,
628: 1-Methyl-3-cis-propylcyclohexylamine,
629: 1-Amino-1-methyl-3 (trans) ethylcyclohexane,
632: 1-Amino-1,3,3-trimethyl-5 (cis) ethylcyclohexane,
633: 1-Amino-1,3,3-trimethyl-5 (trans) ethylcyclohexane,
634: cis-3-Propyl-1,5,5-trimethylcyclohexylamine,
635: trans-3-Propyl-1,5,5-trimethylcyclohexylamine,
639: N-Ethyl-1,3,3,5,5-pentamethylcyclohexylamine,
641: 1-Amino-1-methylcyclohexane,
642: N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,
644: 2-(3,3,5,5-Tetramethylcyclohexyl)ethylamine,
645: 2-Methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,
662: 2-(1,3,3,5,5-Pentamethylcyclohexyl-1) ethylamine, semihydrate,
and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts of any of the foregoing; and such a
method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound in combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers.
Moreover, the use of a 1-aminoalkylcyclohexane selected from the group consisting of those of the formula 
wherein R* is xe2x80x94(CH2)nxe2x80x94(CR6R7)mxe2x80x94NR8R9 
wherein n+m=0, 1, or 2
wherein R1 through R7 are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C), wherein R8 and R9 are independently selected from the group consisting of hydrogen and lower-alkyl or together represent lower-alkylene xe2x80x94(CH2)xxe2x80x94 wherein x is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically-acceptable salts thereof, in the manufacture of a medicament to treat a living animal for alleviation or elimination of trypanosomiasis; such a
use wherein at least R1, R4, and R5 are lower-alkyl; such a
use wherein R1 through R5 are methyl; such a
use wherein x is 4 or 5; such a
use wherein the compound is selected from the group consisting of
580: 3,3,5,5-Tetramethylcyclohexylmethylamine,
601: 1-Amino-1-propyl-3,3,5,5-tetramethylcyclohexane,
607: 1-Amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),
614: 3-Propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate (mixture of diastereomers xcx9c1:2)
615: 1-Amino-1,3,5,5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers),
617: 1-Amino-1,3-dimethyl-3-propylcyclohexane (mixture of diastereomers),
618: 1-Amino-1,3 (trans),5 (trans)-trimethyl-3(cis)-propylcyclohexane,
620: 1-Amino-1,3-dimethyl-3-ethylcyclohexane,
621: 1-Amino-1,3,3-trimethylcyclohexane,
622: cis-3-Ethyl-1, trans-3, trans-5-trimethylcyclohexamine,
625: 1-Amino-1,3 (trans)-dimethylcyclohexane,
626: 1,3,3-Trimethyl-5,5-dipropylcyclohexylamine,
627: 1-Amino-1-methyl-3 (trans) propylcyclohexane,
628: 1-Methyl-3-cis-propylcyclohexylamine,
629: 1-Amino-1-methyl-3 (trans) ethylcyclohexane,
632: 1-Amino-1,3,3-trimethyl-5 (cis) ethylcyclohexane,
633: 1-Amino-1,3,3-trimethyl-5 (trans) ethylcyclohexane,
634: cis-3-Propyl-1,5,5-trimethylcyclohexylamine,
635: trans-3-Propyl-1,5,5-trimethylcyclohexylamine,
639: N-Ethyl-1,3,3,5,5-pentamethylcyclohexylamine,
641: 1-Amino-1-methylcyclohexane,
642: N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, .H2O
644: 2-(3,3,5,5-Tetramethylcyclohexyl)ethylamine,
645: 2-Methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,
662: 2-(1,3,3,5,5-Pentamethylcyclohexyl-1) ethylamine, semihydrate,
and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts of any of the foregoing.
Background and Pharmacoloqy
Some of us reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. In this patent application, we describe the trypanocidal properties of aminoalkylcyclohexane derivatives. Six of the compounds were found to inhibit growth in vitro of bloodstream form T. brucei by greater than 90% at concentrations in the range 0.3-0.7 xcexcg mlxe2x88x921. A correlation between structural features of the derivatives and their trypanocidal properties was observed; hydrophobic substitutions generally enhanced activity.
Synthesis
The synthesis of the novel amino-alkylcyclohexanes which are utilized according to the present invention has been described in U.S. Pat. No. 6,034,134 of Mar. 7, 2000.
Alternative Procedure
The 1-cyclic amino compounds may also be prepared by reacting the corresponding 1-free amino-alkylcyclohexane and the selected alpha, omega-dihaloalkyl compound, e.g., 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane, according to the following representative example:
N-(1,3,3,5,5-Pentamethylcvclohexyl)pyrrolidine Hydrochloride
1,3,3,5,5-pentamethylcyclohexylamine hydrochloride (12 g, 58.3 mmol), potassium carbonate (48.4 g, 350 mmol) and 1,4-dibromobutane (7.32 ml, 61.3 mmol) were refluxed in acetonitrile (250 ml) for 60 h. After cooling to r.t., the mixture was filtered and the precipitate was washed with diethyl ether (600 ml). The filtrate was concentrated in vacuo by rotary evaporation and the residue was fractionally distilled at reduced pressure (11 mm/Hg). The fraction at 129xc2x0 C. was collected to obtain colorless oil (8.95 g). This was dissolved in diethyl ether (120 ml) and 2.7 M HCl solution in diethyl ether (30 ml) was added. The resulting precipitate was filtered off, washed with diethyl ether (3*30 ml) and dried in vacuo over NaOH to give N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine hydrochloride hydrate (12.9 g, 68%) with m.p. 158xc2x0 C. PMR spectrum: (DMSO-d6, TMS) d: 0.97 (6H, s, 3,5-CH3); 1.11 (6H,s, 3,5-CH3); 0.8-1.4 (2H, cyclohexane 4-CH2) 1.41 (3H, s, 1-CH3); 1.69 (4H, m, cyclohexane 2,6-CH2); 1.84 (4H, m, pyrrolidine 3,4-CH2); 3.20 (4H, m, pyrrolidine 2,5-CH2); 10.9 ppm (1H, br s, NH+). Elemental analysis (C15H29n*HCl*H20) Found (%) C 65.0; H 11.7; N5.0 Calculated (%) C 64.8; H 11.6; N 5.0.
Parasites and Drug Testing in vitro
Bloodstream form T-brucei (strain 427) were cultured in 25 cm3 flasks at 37xc2x0 C. in modified Iscove""s medium (pH 7.4). To establish the extent of trypanocidal activity, parasites were grown for three days in the presence of test compounds (aminoalkylcyclohexane derivatives) and the concentrations which inhibited growth by 50%(IC50) and 90%(IC90) were determined. In these experiments, which were performed at least in triplicate, the density of untreated cultures increased from 0.25xc3x97105 cells mlxe2x88x921 to 4xc3x97106 cells mlxe2x88x921. After determination of cell densities at each drug concentration using a hemocytometer (Weber Scientific International Ltd), drug sensitivity was expressed as a percentage of growth of control cells.
Results
Table A shows the general structure of selected amino-alkylcyclohexanes used in the present study.
Substitutions in brackets represent alternatives in racemic mixtures, e.g., CH3(C3H7) means CH3 or C3H7.
Testing in vitro
In a preliminary screen, bloodstream form T.brucei were cultured for 3 days in growth medium at pH 7.4 in the presence of aminoalkylcyclohexane derivatives at a concentration of 5 xcexcg mlxe2x88x921. A range of activities was observed with the compounds tested. The compounds which inhibited growth by 90% or greater were then tested further to determine their IC50s and IC90s. Several of the compounds were found to have appreciable trypanocidal activity. In some cases, this was more than 10 times greater than had previously been observed with xcex1-methyl-1-adamantane methylamine.
The effects of a number of aminoalkylcyclohexane derivatives on cultured bloodstream form T.brucei were investigated. The three most active of these compounds share structural similarities with each other, having aminoethyl (662 and 644xe2x80x94cf. Table 1) or aminomethylpropyl (645xe2x80x94cf. Table 1) groups attached to the cyclohexane ring at position 1. They also have dimethyl substitutions at the 3 and 5 positions, a feature present in other derivatives (580, 601 and 639xe2x80x94cf. Table 1) found to have an IC90 of less than 2 xcexcg mlxe2x88x921. It can also be seen from our data that the presence of dipropyl side chains, as in compound 626 (cf. Table 1), greatly increases the trypanocidal activity.
Discussion
The pharmacological activity of aminoalkylcyclohexane derivatives is representatively identified in Table 1.
An essential requirement for trypanocidal activity in the alkylcyclohexane derivatives is possession of an amino group. This can be attached directly to the cyclohexane ring or be attached via a side chain at the 1 position. Compounds in which the amino group is attached only to a cyclohexane ring also exhibited considerable toxicity to trypanosomes. See Table 1.
The trypanocidal properties of aminoalkylcyclohexane compounds were enhanced by the addition of a bulky side group at position 3. A cyclohexane ring suggests that increased hydrophobicity may be an important factor in determining the activity. There was a significant correlation between hydrophobicity and trypanocidal activity with aminoalkylcyclohexanes (compare compounds 626 and 620; Table 1).
The Table Representative Results
Table 1 Cultured bloodstream form T. brucci were incubated at 37xc2x0 for 3 days in the presence of aminoalkylcyclohexane derivatives. Initially each compound was screened to determine the inhibitory effect at 5 xcexcg mlxe2x88x921 (data in brackets). For the more active compounds, the concentrations that inhibited growth by 50% and 90% were then evaluated. Each experiment was performed in triplicate, except where indicated (++). These data were obtained from six experiments. Values are presented as xc2x1SD from the mean. Where stock compounds (20 mg mlxe2x88x921) were dissolved in DMSO that are indicated as (*) and (#) indicates that they were dissolved in 50:50 (v/v) EtOH:H2O. All other compounds were dissolved in H2O. Control cells were treated accordingly. ND stands for not done.
The active anti-trypanosomiasis agents of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing twenty (20) to one hundred (100) milligrams of active ingredient or, more broadly, ten (10) to two hundred fifty (250) milligrams per tablet, are accordingly representative unit dosage forms.
Due to their high degree of anti-trypanosomiasis activity and their relatively low toxicity, together presenting a favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Dosage ranges may be 1-1000 milligrams daily, preferably 10-500 milligrams daily, and especially 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow.
(a) Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.